Parkinson's disease is a neurodegenerative disease that strikes men and women alike. It is estimated that it affects about 15 out of 10,000 individuals and usually it first appears at an age of about 55-60 years. Despite considerable efforts, the reason for the symptom-causing degeneration of the midbrain dopamine neurons in patients afflicted by this crippling, non-curable disorder is not known. Moreover, while many of the symptoms of Parkinson's disease can be mimicked by lesions or neurotoxin administration to experimental animals, the disease itself is not known in any other species than man, thus hampering research aimed at understanding the etiology and the development of new therapies.
Exposure to toxic compounds in the environment remains one hypothetical cause of the disease although epidemiological studies have generated few clues as to its etiology. More recently, an interest in familial forms of the disease has indicated the presence of genetic components and linkage to an area on chromosome 4 has been reported and is discussed in more detail below.
Thus, in recent linkage studies, autosomal dominant or autosomal recessive types of Parkinson's disease have been mapped to several different loci in the human genome. Although these types of Parkinson's disease often differ from sporadic Parkinson's disease and constitute only a small fraction of the total patient population, the reported loci might confer susceptibility also for idiopatic forms of Parkinson's disease.
Polymeropoulos et al. (Science 274, p. 1197 (1996)) mapped autosomal dominant Parkinson to chromosome 4q21-q23. They called this area “PARK1”. Later, they found a mutation in the gene for alpha-synuclein which segregated with the disease in one large Italian and three Greek kindreds and which they could not find in healthy control individuals. A mutation in the α-synuclein gene was identified in the families with Parkinson's disease (Polymeropoulos et al., Science 276, p. 2045-2047 (1997)). However, in spite of large efforts by other groups to find synuclein mutations in their own patients, they failed to identify any mutations in the alpha-synuclein gene in their material.
Interestingly, Vaughan et al. (Hum. Mol. Genet. 7, 751 (1998)) have reported one German family with autosomal dominant Parkinsonian to show linkage to the PARK1 region 4q21-q23. In this family, no mutations in alpha-synuclein could be identified. Said authors suggest that there might be another gene in the same locus that might account for the disease. In this case, the synuclein mutation in the Italian and Greek kindreds may be a marker that segregates with the “true” disease gene.
In WO 00/00621 the human gene encoding alcohol dehydrogenase 7 (ADH7) was shown to be associated with the development of Parkinson's disease and Parkinson related mutations (M1-M7) in the wildtype ADH7 gene were identified.
Alcohol dehydrogenases (ADH) are zinc metalloenzymes that oxidize alcohols to aldehydes or ketones. In addition to ethanol these enzymes also make important modifications to retinol, steroids, and fatty acids. The mammalian ADH system is divided into six classes, ADH1-ADH6, whereof five have been identified in man. ADH1C (formerly known as ADH3) is located within a cluster of alcoholdehydrogenases on human chromosome 4q21-q23. ADH1C is involved in retinoic acid synthesis from retinal. Since retinoic acid is likely to be of importance for dopamine neuron development and maintenance, genetic disturbances in these enzymes may render dopamine neurons of carriers more susceptible to stressors and may thus enhance the deleterious effects of environmental toxins.
Parkinson's disease is complex and the causes of the disease are multiple. Genetic mutations in alcohol or aldehyde dehydrogenases may constitute heritable risk factors for Parkinson's disease and can provide a link between endogenous metabolic pathways and the outside world (such as dietary retinal and toxic aldehydes). Thus, the more genetic mutations identified, the bigger the chance to develop a reliable diagnostic and prognostic tool for the disease.
Today there is no way of predicting or diagnosing Parkinson's disease prior to the onset of the symptoms. When symptoms occur, patients have typically already lost a very large number, in reality, the majority, of their dopamine nerve cells. Accordingly, a method for prediction and early diagnosis of Parkinson's disease would be very valuable.